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Modulation of androgen receptor function by brominated flame retardants
Örebro University, School of Science and Technology, Örebro University, Sweden.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Örebro: Örebro university , 2015. , 78 p.
Series
Örebro Studies in Biology, ISSN 1650-8793 ; 13
Keyword [en]
DBE-DBCH, TBP-AE, TBP-BAE, TBP-DBPE, androgen receptor, endocrine disrupters, brominated flame retardant
National Category
Biological Sciences
Research subject
Biology
Identifiers
URN: urn:nbn:se:oru:diva-43881ISBN: 978-91-7529-082-9 (print)OAI: oai:DiVA.org:oru-43881DiVA: diva2:798414
Public defence
2015-06-05, Hörsalen, Musikhögskolan, Örebro universitet, Fakultetsgatan 1, Örebro, 10:00 (English)
Opponent
Supervisors
Available from: 2015-03-26 Created: 2015-03-26 Last updated: 2016-12-13Bibliographically approved
List of papers
1. Identification of a group of brominated flame retardants as novel androgen receptor antagonists and potential neuronal and endocrine disrupters
Open this publication in new window or tab >>Identification of a group of brominated flame retardants as novel androgen receptor antagonists and potential neuronal and endocrine disrupters
Show others...
2015 (English)In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 74, 60-70 p.Article in journal (Refereed) Published
Abstract [en]

Brominated flame-retardants (BFRs) are used in industrial products to reduce the risk of fire. However, their continuous release into the environment is a concern as they are often persistent, bioaccumulating and toxic. Information on the impact these compounds have on human health and wildlife is limited and only a few of them have been identified to disrupt hormone receptor functions. In the present study we used in silico modeling to determine the interactions of selected BFRs with the human androgen receptor (AR). Three compounds were found to dock into the ligand-binding domain of the human AR and these were further tested using in vitro analysis. Allyl 2,4,6-tribromophenyl ether (ATE), 2-bromoallyl 2,4,6-tribromophenyl ether (BATE) and 2,3-dibromopropyl-2,4,6-tribromophenyl ether (DPTE) were observed to act as AR antagonists. These BFRs have recently been detected in the environment, in house dust and in aquatic animals. The compounds have been detected at high concentrations in both blubber and brain of seals and we therefore also assessed their impact on the expression of L-type amino acid transporter system (LAT) genes, that are needed for amino acid uptake across the blood-brain barrier, as disruption of LAT gene function has been implicated in several brain disorders. The three BFRs down-regulated the expression of AR target genes that encode for prostate specific antigen (PSA), 5. α-reductases and β-microseminoprotein. The potency of PSA inhibition was of the same magnitude as the common prostate cancer drugs, demonstrating that these compounds are strong AR antagonists. Western blot analysis of AR protein showed that ATE, BATE and DPTE decreased the 5. α-dihydrotestosterone-induced AR protein levels, further confirming that these BFRs act as AR antagonists. The transcription of the LAT genes was altered by the three BFRs, indicating an effect on amino-acid uptake across cellular membranes and blood-brain barrier. This study demonstrated that ATE, BATE and DPTE are potent AR antagonists and the alterations in LAT gene transcription suggest that these compounds can affect neuronal functions and should be considered as potential neurotoxic and endocrine disrupting compounds.

Keyword
Gene regulation; Human; PSA; LAT
National Category
Environmental Sciences
Research subject
Biology
Identifiers
urn:nbn:se:oru:diva-41508 (URN)10.1016/j.envint.2014.09.002 (DOI)000346681700008 ()25454221 (PubMedID)2-s2.0-84908626070 (Scopus ID)
Funder
Knowledge Foundation, 20110183
Note

Funding Agency:

Örebro University J61900

Available from: 2015-01-14 Created: 2015-01-14 Last updated: 2016-12-14Bibliographically approved
2. The brominated flame retardant TBECH activates the zebrafish (Danio rerio) androgen receptor, alters gene transcription and causes developmental disturbances
Open this publication in new window or tab >>The brominated flame retardant TBECH activates the zebrafish (Danio rerio) androgen receptor, alters gene transcription and causes developmental disturbances
2013 (English)In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 142, 63-72 p.Article in journal (Refereed) Published
Abstract [en]

Tetrabromoethylcyclohexane (TBECH) is a brominated flame retardant that has been shown to be a potent agonist to the human androgen receptor (AR). However, while it is present in the environment, it is not known if it interacts with AR from aquatic species. The present study was therefore aimed at improving our understanding of how TBECH affects aquatic animals using zebrafish as a model organism. In silica modeling demonstrated that TBECH diastereomers bind to the zebrafish androgen receptor (zAR) and in vitro and in vivo data showed that TBECH has androgenic properties. Deleterious effects of TBECH were studied on embryonic and juvenile zebrafish and qRT-PCR analysis in vitro and in vivo was performed to determine TBECH effects on gene regulation. TBECH was found to delay hatching at 1 mu M and 10 mu M doses while morphological abnormalities and juvenile mortality was observed at 10 mu M. The qRT-PCR analysis showed alterations of multiple genes involved in chondrogenesis (cartilage development), metabolism and stress response. Thus, TBECH induces androgenic activity and has negative effects on zebrafish physiology and therefore its impact on the environment should be carefully monitored. (C) 2013 Elsevier B.V. All rights reserved.

Keyword
Androgens, Endocrine, Endocrine disruptor, Gene regulation
National Category
Biological Sciences
Identifiers
urn:nbn:se:oru:diva-32902 (URN)10.1016/j.aquatox.2013.07.018 (DOI)000328093900007 ()23958786 (PubMedID)
Funder
Knowledge Foundation
Available from: 2014-01-02 Created: 2014-01-02 Last updated: 2016-12-14Bibliographically approved
3. Androgen receptor mutations associated with prostate cancer lead to differential activation by DBE-DBCH diastereomers
Open this publication in new window or tab >>Androgen receptor mutations associated with prostate cancer lead to differential activation by DBE-DBCH diastereomers
(English)Manuscript (preprint) (Other academic)
Keyword
steroid hormone receptor, endocrine disruptor, human carcinoma, androgen agonists
National Category
Biological Sciences
Research subject
Biology
Identifiers
urn:nbn:se:oru:diva-44665 (URN)
Available from: 2015-05-20 Created: 2015-05-20 Last updated: 2016-12-14Bibliographically approved
4. Combination effects on human cell lines following exposure to brominated flame-retardants that interact with the androgen receptor
Open this publication in new window or tab >>Combination effects on human cell lines following exposure to brominated flame-retardants that interact with the androgen receptor
(English)Manuscript (preprint) (Other academic)
Keyword
DBE-DBCH/TBECH, TBP-AE/ATE, TBP-BAE/BATE, TBP-DBPE/DPTE, endocrine disruptors, PSA, steroidogenesis
National Category
Biological Sciences
Research subject
Biology
Identifiers
urn:nbn:se:oru:diva-44666 (URN)
Available from: 2015-05-20 Created: 2015-05-20 Last updated: 2016-12-13Bibliographically approved

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